Chymase, a chymotrypsin-like serine protease discovered in 1975, is released upon mast cell degranulation. Although it is known that chymase is able to cleave extracellular matrix and other biologically active substances, much attention has been given to its ability to convert angiotensin I, in a manner independent of that of angiotensin-converting enzyme, to the vasoconstrictor angiotensin II. Previous studies have suggested that the formation of angiotensin II within the human heart is mainly controlled by chymase rather than by angiotensin-converting enzyme [Circ. Res. 66, 883-890 (1990)]. Accordingly, it has been assumed that chymase plays an important role in the progression of cardiovascular diseases such as cardiac hypertrophy, myocardial infarction, vascular hyperplasia, and restenosis following angioplasty.
Moreover, it has been shown that chymase enhances histamine release from mast cells and induces a prolonged increase in microvascular permeability independent of histamine [Eur. J. Pharmacol. 352, 91-98 (1998)]. It is, therefore, highly possible that chymase plays an important role, not only in the immediate type of allergic inflammatory reactions, but also in the delayed ones, which are known to involve mast cells.
Mast cells containing chymase as well as tryptase are mainly distributed in connective tissues, while those containing tryptase, but not chymase, are mainly present in mucosal tissues. In addition, it has been reported that chymase activity increases significantly with the progression of tissue fibrosis including intraperitoneal adhesion formation [FEBS Letters 406, 301-304 (1997), J. Surg. Res. 92, 40-44 (2000)]. These findings indicate that chymase may participate in tissue fibrosis.
In addition to its possible involvement in a range of diseases and complications, chymase is known to have various other physiological activities such as, formation of other active proteases for matrix degradation, activation of the inflammatory cytokine IL-1 β precursor, formation of the active TGF-β in fibrosis, enhancement of foam cell formation and maintenance in atherogenesis, and conversion of big endothelins to contractile 31-amino acid length endothelins. Accordingly, it is suggested that chymase may play an important role in blood flow regulation, allergy, inflammation, and tissue remodeling. Combining the information above, it is expected that chymase inhibitors, acting as antiallergic, antiinflammatory, antirestenotic, or antiarteriosclerotic agents, may provide novel treatments for a wide range of diseases and complications.
Studies have hitherto been made for finding an excellent chymase inhibitor, and there are reported various kinds of chymase inhibitors, for example, it is disclosed in WO-A-93/25574 that a wide range of compounds have a chymase inhibitory activity, but no specific data of the activity is disclosed. WO-A-93/25574 includes very broad claims and discloses 28 examples, among which the compound of Example 21 has the following formula (A): 
In the following formula (I) of the present compounds, the above compound (A) is not includes. That is, R3 of the following formula (I) means an unsaturated monocyclic heterocyclic group, but not a saturated monocyclic heterocyclic group. In addition, as disclosed in Experiments as described below, the chymase inhibitory activity of the compound (A) is far weaker than that of the present compounds.